From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Identifieur interne : 002815 ( Main/Exploration ); précédent : 002814; suivant : 002816From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Auteurs : Kiran Musunuru [États-Unis] ; Alanna Strong [États-Unis] ; Maria Frank-Kamenetsky [États-Unis] ; Noemi E. Lee [États-Unis] ; Tim Ahfeldt [États-Unis, Allemagne] ; Katherine V. Sachs [États-Unis] ; Xiaoyu Li [États-Unis] ; Hui Li [États-Unis] ; Nicolas Kuperwasser [États-Unis] ; Vera M. Ruda [États-Unis] ; James P. Pirruccello [États-Unis] ; Brian Muchmore [États-Unis] ; Ludmila Prokunina-Olsson [États-Unis] ; Jennifer L. Hall [États-Unis] ; Eric E. Schadt [États-Unis] ; Carlos R. Morales [Canada] ; Sissel Lund-Katz [États-Unis] ; Michael C. Phillips [États-Unis] ; Jamie Wong [États-Unis] ; William Cantley [États-Unis] ; Timothy Racie [États-Unis] ; Kenechi G. Ejebe [États-Unis] ; Marju Orho-Melander [Suède] ; Olle Melander [Suède] ; Victor Koteliansky [États-Unis] ; Kevin Fitzgerald [États-Unis] ; Ronald M. Krauss [États-Unis] ; Chad A. Cowan [États-Unis] ; Sekar Kathiresan [États-Unis] ; Daniel J. Rader [États-Unis]Source :
- Nature [ 0028-0836 ] ; 2010-08-05.
Abstract
Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.
A non-coding polymorphism at a locus associated with myocardial infarction in humans creates a CCAAT/enhancer binding protein transcription factor binding site and alters the hepatic expression of the SORT1 gene. These authors show that modulating Sort1 levels in mouse liver alters levels of plasma low-density lipoprotein cholesterol and very low-density lipoprotein, potentially explaining why polymorphisms at this locus are associated with heart disease.
Url:
DOI: 10.1038/nature09266
Affiliations:
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Hall</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Broad Institute, Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Cardiovascular Translational Genomics, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea><wicri:noRegion>Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Schadt, Eric E" sort="Schadt, Eric E" uniqKey="Schadt E" first="Eric E." last="Schadt">Eric E. 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Morales</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Lund Katz, Sissel" sort="Lund Katz, Sissel" uniqKey="Lund Katz S" first="Sissel" last="Lund-Katz">Sissel Lund-Katz</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104</wicri:regionArea><wicri:noRegion>Pennsylvania 19104</wicri:noRegion></affiliation></author><author><name sortKey="Phillips, Michael C" sort="Phillips, Michael C" uniqKey="Phillips M" first="Michael C." last="Phillips">Michael C. Phillips</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104</wicri:regionArea><wicri:noRegion>Pennsylvania 19104</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Jamie" sort="Wong, Jamie" uniqKey="Wong J" first="Jamie" last="Wong">Jamie Wong</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Cantley, William" sort="Cantley, William" uniqKey="Cantley W" first="William" last="Cantley">William Cantley</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Racie, Timothy" sort="Racie, Timothy" uniqKey="Racie T" first="Timothy" last="Racie">Timothy Racie</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Ejebe, Kenechi G" sort="Ejebe, Kenechi G" uniqKey="Ejebe K" first="Kenechi G." last="Ejebe">Kenechi G. Ejebe</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea><wicri:noRegion>Massachusetts 02114</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Broad Institute, Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Orho Melander, Marju" sort="Orho Melander, Marju" uniqKey="Orho Melander M" first="Marju" last="Orho-Melander">Marju Orho-Melander</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Sciences, Skania University Hospital, Lund University, SE-20502 Malmö</wicri:regionArea><wicri:noRegion>SE-20502 Malmö</wicri:noRegion></affiliation></author><author><name sortKey="Melander, Olle" sort="Melander, Olle" uniqKey="Melander O" first="Olle" last="Melander">Olle Melander</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Sciences, Skania University Hospital, Lund University, SE-20502 Malmö</wicri:regionArea><wicri:noRegion>SE-20502 Malmö</wicri:noRegion></affiliation></author><author><name sortKey="Koteliansky, Victor" sort="Koteliansky, Victor" uniqKey="Koteliansky V" first="Victor" last="Koteliansky">Victor Koteliansky</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Fitzgerald, Kevin" sort="Fitzgerald, Kevin" uniqKey="Fitzgerald K" first="Kevin" last="Fitzgerald">Kevin Fitzgerald</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Krauss, Ronald M" sort="Krauss, Ronald M" uniqKey="Krauss R" first="Ronald M." last="Krauss">Ronald M. Krauss</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Children’s Hospital Oakland Research Institute, Oakland, California 94609</wicri:regionArea><wicri:noRegion>California 94609</wicri:noRegion></affiliation></author><author><name sortKey="Cowan, Chad A" sort="Cowan, Chad A" uniqKey="Cowan C" first="Chad A." last="Cowan">Chad A. Cowan</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea><wicri:noRegion>Massachusetts 02114</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Broad Institute, Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Kathiresan, Sekar" sort="Kathiresan, Sekar" uniqKey="Kathiresan S" first="Sekar" last="Kathiresan">Sekar Kathiresan</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea><wicri:noRegion>Massachusetts 02114</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Broad Institute, Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation><affiliation></affiliation><affiliation></affiliation></author><author><name sortKey="Rader, Daniel J" sort="Rader, Daniel J" uniqKey="Rader D" first="Daniel J." last="Rader">Daniel J. Rader</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104</wicri:regionArea><wicri:noRegion>Pennsylvania 19104</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Nature</title><idno type="ISSN">0028-0836</idno><idno type="eISSN">1476-4687</idno><imprint><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><date when="2010-08-05">2010-08-05</date><biblScope unit="vol">466</biblScope><biblScope unit="issue">7307</biblScope><biblScope unit="page" from="714">714</biblScope><biblScope unit="page" to="719">719</biblScope><date type="Copyright" when="2010">2010</date></imprint><idno type="ISSN">0028-0836</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0028-0836</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="eng">Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.</div><div type="abstract" xml:lang="eng">A non-coding polymorphism at a locus associated with myocardial infarction in humans creates a CCAAT/enhancer binding protein transcription factor binding site and alters the hepatic expression of the SORT1 gene. These authors show that modulating Sort1 levels in mouse liver alters levels of plasma low-density lipoprotein cholesterol and very low-density lipoprotein, potentially explaining why polymorphisms at this locus are associated with heart disease.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Canada</li><li>Suède</li><li>États-Unis</li></country><region><li>Hambourg</li><li>Québec</li></region><settlement><li>Hambourg</li><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="États-Unis"><noRegion><name sortKey="Musunuru, Kiran" sort="Musunuru, Kiran" uniqKey="Musunuru K" first="Kiran" last="Musunuru">Kiran Musunuru</name></noRegion><name sortKey="Ahfeldt, Tim" sort="Ahfeldt, Tim" uniqKey="Ahfeldt T" first="Tim" last="Ahfeldt">Tim Ahfeldt</name><name sortKey="Cantley, William" sort="Cantley, William" uniqKey="Cantley W" first="William" last="Cantley">William Cantley</name><name sortKey="Cowan, Chad A" sort="Cowan, Chad A" uniqKey="Cowan C" first="Chad A." last="Cowan">Chad A. Cowan</name><name sortKey="Cowan, Chad A" sort="Cowan, Chad A" uniqKey="Cowan C" first="Chad A." last="Cowan">Chad A. Cowan</name><name sortKey="Ejebe, Kenechi G" sort="Ejebe, Kenechi G" uniqKey="Ejebe K" first="Kenechi G." last="Ejebe">Kenechi G. Ejebe</name><name sortKey="Ejebe, Kenechi G" sort="Ejebe, Kenechi G" uniqKey="Ejebe K" first="Kenechi G." last="Ejebe">Kenechi G. Ejebe</name><name sortKey="Fitzgerald, Kevin" sort="Fitzgerald, Kevin" uniqKey="Fitzgerald K" first="Kevin" last="Fitzgerald">Kevin Fitzgerald</name><name sortKey="Frank Kamenetsky, Maria" sort="Frank Kamenetsky, Maria" uniqKey="Frank Kamenetsky M" first="Maria" last="Frank-Kamenetsky">Maria Frank-Kamenetsky</name><name sortKey="Hall, Jennifer L" sort="Hall, Jennifer L" uniqKey="Hall J" first="Jennifer L." last="Hall">Jennifer L. Hall</name><name sortKey="Hall, Jennifer L" sort="Hall, Jennifer L" uniqKey="Hall J" first="Jennifer L." last="Hall">Jennifer L. Hall</name><name sortKey="Kathiresan, Sekar" sort="Kathiresan, Sekar" uniqKey="Kathiresan S" first="Sekar" last="Kathiresan">Sekar Kathiresan</name><name sortKey="Kathiresan, Sekar" sort="Kathiresan, Sekar" uniqKey="Kathiresan S" first="Sekar" last="Kathiresan">Sekar Kathiresan</name><name sortKey="Koteliansky, Victor" sort="Koteliansky, Victor" uniqKey="Koteliansky V" first="Victor" last="Koteliansky">Victor Koteliansky</name><name sortKey="Krauss, Ronald M" sort="Krauss, Ronald M" uniqKey="Krauss R" first="Ronald M." last="Krauss">Ronald M. Krauss</name><name sortKey="Kuperwasser, Nicolas" sort="Kuperwasser, Nicolas" uniqKey="Kuperwasser N" first="Nicolas" last="Kuperwasser">Nicolas Kuperwasser</name><name sortKey="Lee, Noemi E" sort="Lee, Noemi E" uniqKey="Lee N" first="Noemi E." last="Lee">Noemi E. Lee</name><name sortKey="Li, Hui" sort="Li, Hui" uniqKey="Li H" first="Hui" last="Li">Hui Li</name><name sortKey="Li, Xiaoyu" sort="Li, Xiaoyu" uniqKey="Li X" first="Xiaoyu" last="Li">Xiaoyu Li</name><name sortKey="Lund Katz, Sissel" sort="Lund Katz, Sissel" uniqKey="Lund Katz S" first="Sissel" last="Lund-Katz">Sissel Lund-Katz</name><name sortKey="Muchmore, Brian" sort="Muchmore, Brian" uniqKey="Muchmore B" first="Brian" last="Muchmore">Brian Muchmore</name><name sortKey="Musunuru, Kiran" sort="Musunuru, Kiran" uniqKey="Musunuru K" first="Kiran" last="Musunuru">Kiran Musunuru</name><name sortKey="Musunuru, Kiran" sort="Musunuru, Kiran" uniqKey="Musunuru K" first="Kiran" last="Musunuru">Kiran Musunuru</name><name sortKey="Phillips, Michael C" sort="Phillips, Michael C" uniqKey="Phillips M" first="Michael C." last="Phillips">Michael C. Phillips</name><name sortKey="Pirruccello, James P" sort="Pirruccello, James P" uniqKey="Pirruccello J" first="James P." last="Pirruccello">James P. Pirruccello</name><name sortKey="Pirruccello, James P" sort="Pirruccello, James P" uniqKey="Pirruccello J" first="James P." last="Pirruccello">James P. Pirruccello</name><name sortKey="Prokunina Olsson, Ludmila" sort="Prokunina Olsson, Ludmila" uniqKey="Prokunina Olsson L" first="Ludmila" last="Prokunina-Olsson">Ludmila Prokunina-Olsson</name><name sortKey="Racie, Timothy" sort="Racie, Timothy" uniqKey="Racie T" first="Timothy" last="Racie">Timothy Racie</name><name sortKey="Rader, Daniel J" sort="Rader, Daniel J" uniqKey="Rader D" first="Daniel J." last="Rader">Daniel J. Rader</name><name sortKey="Rader, Daniel J" sort="Rader, Daniel J" uniqKey="Rader D" first="Daniel J." last="Rader">Daniel J. Rader</name><name sortKey="Ruda, Vera M" sort="Ruda, Vera M" uniqKey="Ruda V" first="Vera M." last="Ruda">Vera M. Ruda</name><name sortKey="Sachs, Katherine V" sort="Sachs, Katherine V" uniqKey="Sachs K" first="Katherine V." last="Sachs">Katherine V. Sachs</name><name sortKey="Schadt, Eric E" sort="Schadt, Eric E" uniqKey="Schadt E" first="Eric E." last="Schadt">Eric E. Schadt</name><name sortKey="Strong, Alanna" sort="Strong, Alanna" uniqKey="Strong A" first="Alanna" last="Strong">Alanna Strong</name><name sortKey="Wong, Jamie" sort="Wong, Jamie" uniqKey="Wong J" first="Jamie" last="Wong">Jamie Wong</name></country><country name="Allemagne"><region name="Hambourg"><name sortKey="Ahfeldt, Tim" sort="Ahfeldt, Tim" uniqKey="Ahfeldt T" first="Tim" last="Ahfeldt">Tim Ahfeldt</name></region></country><country name="Canada"><region name="Québec"><name sortKey="Morales, Carlos R" sort="Morales, Carlos R" uniqKey="Morales C" first="Carlos R." last="Morales">Carlos R. Morales</name></region></country><country name="Suède"><noRegion><name sortKey="Orho Melander, Marju" sort="Orho Melander, Marju" uniqKey="Orho Melander M" first="Marju" last="Orho-Melander">Marju Orho-Melander</name></noRegion><name sortKey="Melander, Olle" sort="Melander, Olle" uniqKey="Melander O" first="Olle" last="Melander">Olle Melander</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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